Time-course of treatment-emergent adverse events in a long-term safety study of lisdexamfetamine dimesylate in children and adolescents with ADHD

Introduction The long-term safety and efficacy of lisdexamfetamine dimesylate (LDX) in children and adolescents with attention deficit/hyperactivity disorder (ADHD) was evaluated in a European 2-year, open-label study (SPD489-404). Objective To evaluate the time-course of treatment-emergent adverse events (TEAEs) in SPD489-404. Methods Participants aged 6–17 years received open-label LDX (30, 50 or 70 mg/day) for 104 weeks (4 weeks dose-optimization; 100 weeks dose-maintenance). Results All enrolled participants ( n  = 314) were included in the safety population and 191 (60.8%) completed the study. TEAEs occurred in 282 (89.8%) participants; most were mild or moderate. TEAEs considered by the investigators as related to LDX were reported by 232 (73.9%) participants with the following reported for ≥ 10% of participants: decreased appetite (49.4%), weight decreased (18.2%), insomnia (13.1%). TEAEs leading to discontinuation and serious TEAEs occurred in 39 (12.4%) and 28 (8.9%) participants, respectively. The median (range) time to first onset and duration, respectively, of TEAEs identified by the sponsor as being of special interest were: insomnia (insomnia, initial insomnia, middle insomnia, terminal insomnia), 17.0 (1–729) and 42.8 (1–739) days; weight decreased, 29.0 (1–677) and 225.0 (26–724) days; decreased appetite, 13.5 (1–653) and 169.0 (1–749) days; headache, 22.0 (1–718) and 2.0 (1–729) days. Reports of insomnia, weight decreased, decreased appetite and headache were highest in the first 4–12 weeks. Conclusions TEAEs associated with long-term LDX treatment were characteristic of stimulant medications, with the greatest incidence observed during the first 4–12 weeks.